Overnutrition has been consistently identified as a serious health risk by several nutrition/health policy groups including the Food and Nutrition Board of the National Academy of Science, the U.S. Senate Select Committee on Nutrition and Human Needs (Dietary Goals for the United States) and the USDA and DHEW (Nutrition and Your Health: Dietary Guidelines for Americans). The control of obesity will help reduce the economic losses due to coronary heart disease (49 billion per year), the losses due to cancer (72 billion dollars per year), diabetes (13.8 billion dollars per year) and stroke (11 billion dollars per year). The high rate of failure to maintain energy balance has been related to the lack of understanding of the endogenous mechanisms for long term regulation. Most studies have focused on short term control mechanisms, which are overridden by other mechanisms which control body energy balance. Several models of energy balance regulation have been used to identify mechanism of regulation. Over- and underfeeding has been used to establish basic principals of food intake control under condition of long term control. Restricted feeding caused a loss of body fat below the genetically set optimal level and stimulated hunger. Conversely, overfeeding caused an increase in body fat above the genetically set level and resulted in a decrease in feeding response. Central mechanisms for the control of food intake and the regulation of body composition are the focus of this proposal. The main hypothesis to be tested is that metabolic activity within specific areas of the brain may be altered to depict peripheral energy status. In turn, these brain areas may utilize this metabolic information to regulate energy balance through control of food intake, endocrine status and autonomic activity. The objectives of the proposal are as follows: 1) To critically test the hypothesis by directly manipulating hypothalamic metabolic activity and measuring changes in food intake and body composition, 2) to determine the mechanisms by which CNS metabolism influences food intake and body composition through the study of the release of neuropeptides and neurotransmitters, peripheral tissue metabolism and hormone status, 3) to determine the mechanisms by which CNS metabolism directly influences the in vitro release of neuropeptides and neurotransmitters. These studies should provide a basic understanding of energy balance regulation and provide the tools for controlling some forms of obesity.